Methods and compositions for treating SARS-CoV-2 infection using carboxyamidotriazole orotate
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Publication Number
US-11318118-B1
Publication Date
2022-05-03
Expiration Date
Abstract
This invention provides compositions and methods for treatment of mild, moderate and severe stages of SARS-CoV-2 infection, particularly COVID-19 disease caused by wild type and mutant strains of SARS-CoV-2 using 5-amino-1-(4-(4-chlorobenzyl)-1, 2, 3-triazole-4-carboxamide orotate. Carboxyamidotriazole orotate (CTO) alone or in combination with other therapeutics in standard of clinical care are useful for directing antiviral effects and host-directed antiviral effects against wild type and mutant strains of SARS-CoV-2 throughout the viral life cycle.
Core Innovation
The invention describes carboxyamidotriazole orotate, also referred to as the orotate salt of carboxyamidotriazole, as an antiviral and host-directed antiviral therapy for SARS-CoV-2 infection in a human patient. The therapy is described for COVID-19 across mild, moderate, and severe stages, including wild type and mutant SARS-CoV-2, and is directed to inhibiting SARS-CoV-2 virulence and expression together with modulation of host responses associated with disease severity.
The central mechanism is described as modulation of non-voltage-gated calcium signaling, including extracellular and intracellular calcium signaling mediated via membrane, endoplasmic reticulum, and mitochondria. This modulation is stated to inhibit phosphorylation of host and viral proteins, viral entry, viral replication and transcription, and non-lytic release, and to reduce cytokine release and cytokine storm together with downstream effects including coagulation and organ damage.
In addition to inhibiting cytokine storm, the invention is described as increasing selected anti-inflammatory cytokines, including IFN-12 and IL-10, while decreasing inflammatory mediators. The disclosed pathway linkage is supported by plasma cytokine profiling after CTO dosing and in vitro SARS-CoV-2 cytopathic effect inhibition, and the therapy is described as comprising a once daily effective amount of CTO within a range of 50 mg/m2 to 1500 mg/m2 based on body surface area, with the effective amount, formulation type, and route determined according to the patient’s condition and disease stage.
Claims Coverage
The independent claims cover four patient-stage-specific methods and one cytokine-focused method, totaling four independent claims. Across these claims, the core inventive theme is administering a pharmaceutical composition comprising carboxyamidotriazole orotate with a once daily body-surface-area-based dosing range to inhibit SARS-CoV-2-associated processes and/or cytokine and inflammatory outcomes in specified COVID-19 stages.
Mild-stage inhibition of SARS-CoV-2 entry, phosphorylation, replication and propagation
Administering a pharmaceutical composition comprising carboxyamidotriazole orotate to a human patient having a mild stage of COVID-19, wherein the effective amount, formulation type and route are determined as appropriate to the condition to inhibit entry, phosphorylation, replication and propagation of SARS-CoV-2, and wherein the effective amount is a once daily dose of carboxyamidotriazole orotate in the range of 50 mg/m2 to 1500 mg/m2 based on the body surface of the human patient.
Moderate-stage inhibition of cytokine production with inflammatory activity
Administering a pharmaceutical composition comprising carboxyamidotriazole orotate to a human patient having a moderate stage of COVID-19, wherein the effective amount, formulation type and route are determined as appropriate to the condition to inhibit production of cytokines with inflammatory activity, with the effective amount being a once daily dose in the range of 50 mg/m2 to 1500 mg/m2 based on the body surface of the human patient, and wherein the cytokines comprise VEGF, GM-CSF, INF-13, IL-2, IL-12p70, IL-13, IL-15, IL-17a, IL-1RA, IL-11, IL-2, IL-4, IL-6, IL-8, IL-10, MIP1-1, IL-12 and TNF-1.
Moderate-stage treatment to increase interferon-2a antiviral activity and IL-10 anti-inflammatory activity
Administering a pharmaceutical composition comprising carboxyamidotriazole orotate to a human patient having a moderate stage of COVID-19, wherein the effective amount, formulation type and route are determined as appropriate to the condition to increase production of interferon-2a with antiviral activity and IL-10 with anti-inflammatory activity, and wherein the effective amount is a once daily dose of carboxyamidotriazole orotate in the range of 50 mg/m2 to 1500 mg/m2 based on the body surface of the human patient.
Severe-stage inhibition of cytokines, hyperinflammation, coagulation, and organ damage
Administering a pharmaceutical composition comprising carboxyamidotriazole orotate to a human patient having a severe stage of COVID-19, wherein the effective amount, formulation type and route are determined as appropriate to the condition to inhibit production of cytokines, inhibit hyperinflammation, inhibit coagulation, and inhibit damage to organs including heart, liver, kidneys, brain and lungs, and wherein the effective amount is a once daily dose of carboxyamidotriazole orotate in the range of 50 mg/m2 to 1500 mg/m2 based on the body surface of the human patient.
Across the independent claims, the inventive coverage is directed to stage-specific administration of carboxyamidotriazole orotate with a once daily 50 mg/m2 to 1500 mg/m2 body-surface-area-based dosing range, with determination of formulation type and route according to patient condition, for inhibiting SARS-CoV-2-associated processes in mild disease, suppressing inflammatory cytokine production in moderate disease, increasing interferon-2a and IL-10 production in moderate disease, and inhibiting cytokine production, hyperinflammation, coagulation, and organ damage in severe disease.
Stated Advantages
Inhibiting entry, phosphorylation, replication and propagation of SARS-CoV-2 in mild-stage COVID-19.
Inhibiting production of cytokines with inflammatory activity, including multiple named inflammatory cytokines, in moderate-stage COVID-19.
Increasing production of interferon-2a with antiviral activity and IL-10 with anti-inflammatory activity in moderate-stage COVID-19.
Inhibiting production of cytokines, hyperinflammation, coagulation, and damage to organs including heart, liver, kidneys, brain and lungs in severe-stage COVID-19.
Documented Applications
Treatment of COVID-19 in human patients across mild, moderate, and severe stages using carboxyamidotriazole orotate to inhibit SARS-CoV-2 virulence and expression and modulate disease-associated cytokines and inflammatory outcomes.
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